Neisseria gonorrhoeae ciprofloxacin susceptibility testing and gyrA targets
Authors: Jacob A Tickner, Ella Trembizki, David M Whiley
Journal: The Lancet Microbe (2023)

Molecular assays for identifying ciprofloxacin susceptibility via the Neisseria gonorrhoeae gyrA codon 91 are now available. Rubin and colleagues1Rubin DHF Mortimer TD Grad YH Neisseria gonorrhoeae diagnostic escape from a gyrA-based test for ciprofloxacin susceptibility and the effect on zoliflodacin resistance: a bacterial genetics and experimental evolution study.Lancet Microbe. 2023; 4: e247-e254Summary Full Text Full Text PDF PubMed Scopus (2) Google Scholar present data exploring the possibility of diagnostic escape from gyrA codon 91-based ciprofloxacin susceptibility testing, and conclude that escape could occur through either reversion of the gyrA allele or expansion of circulating N gonorrhoeae lineages. The authors also highlight concerns over coselection of zoliflodacin resistance via alternative mechanisms such as gyrB D429N. Although we do not question the validity of the scientific approaches used, we further highlight that the work is theoretical, and that there are no data to suggest that any N gonorrhoeae gyrA codon 91-based diagnostic methods should be modified to accommodate these findings. A key finding was that three N gonorrhoeae clinical isolates with wildtype gyrA codon 91, but with recognised resistance-associated substitutions at gyrA codon 95 maintained intermediate ciprofloxacin minimum inhibitory concentrations (MIC) of 0·125–0·500 μg/mL. Although the observed gyrA codon 95 mutations can indeed produce an intermediate range MIC, our assessment of the literature is that the data regarding intermediate ciprofloxacin MIC and risk of treatment failure are in fact scarce and, at best, warrant further investigation.2Chaudry AE Klausner JD A narrative review of clinical treatment outcomes of Neisseria gonorrhoeae infection with ciprofloxacin by minimum inhibitory concentration and anatomic site.Sex Transm Dis. 2021; 48: 385-392PubMed Google Scholar The authors state that a test that identifies both codons 91 and 95 would be less likely to select for reversion to the susceptible allele, as all strains with gyrA wildtype 91S/95D remained highly susceptible to ciprofloxacin. Although we appreciate the authors' reasoning, we are not convinced that the data presented necessarily warrant diagnostics that incorporate both the 91 and 95 codon, particularly given the rarity at which isolates with wildtype codon 91 and mutant codon 95 appear to occur. The data showing selection strains gaining gyrB D429N substitutions via an experimental evolution approach also need to be interpreted with caution; however, the authors appropriately acknowledge that the in vivo viability and diagnostic utility of this mutation is not known. A key advantage of the single-target (91S) approaches is their simplicity, making assay development more feasible from a design and commercialisation perspective. For this reason, we warn against unnecessarily increasing diagnostic complexity. The interplay of emerging gonococcal antimicrobial resistance, fitness, and potential for sustained transmission is complex, and predicting future outcomes is very difficult. Hence, decisions to change established targets should only occur once a problematic strain is shown to have sufficient fitness for dissemination by reliable surveillance data, to present a real (as opposed to theoretical) clinical problem. We report research funding from SpeeDx. Note that SpeeDx has specific interest related to resistance-guided therapy. SpeeDx did not have any role in the conception or drafting of this manuscript. Neisseria gonorrhoeae diagnostic escape from a gyrA-based test for ciprofloxacin susceptibility and the effect on zoliflodacin resistance: a bacterial genetics and experimental evolution studyDiagnostic escape from gyrA codon 91 diagnostics could occur through either reversion of the gyrA allele or expansion of circulating lineages. N gonorrhoeae genomic surveillance efforts might benefit from including gyrB, given its potential for contributing to ciprofloxacin and zoliflodacin resistance, and diagnostic strategies that reduce the likelihood of escape, such as the incorporation of multiple target sites, should be investigated. Diagnostics that guide antibiotic therapy can have unintended consequences, including novel resistance determinants and antibiotic cross-resistance. Full-Text PDF Open AccessNeisseria gonorrhoeae ciprofloxacin susceptibility testing and gyrA targets – Authors' replyWe agree with Jacob A Tickner and colleagues that diagnostics that predict Neisseria gonorrhoeae susceptibility to ciprofloxacin based on gyrA codon 91 are valuable tools in the effort to treat gonorrhoea and to address the challenge of antimicrobial resistance. But will these diagnostic tests always have the sensitivity and specificity that they have today? The premise of our work is that a diagnostic that guides antibiotic use will itself apply a selective pressure to escape from that diagnostic, under the same principle as antibiotics selecting for resistance. Full-Text PDF Open Access